Topoisomerases control the level of DNA supercoiling in cells and are vital for most cellular processes involving DNA. Human topoisomerase I (topo I) is a 91 kD enzyme that breaks one strand of duplex DNA, forming a transient phosphotyrosine bond with the broken strand, and catalyzes the relaxation of both positive and negative supercoils about the intact strand. Human topo I is the target of the camptothecins, a promising class of anti-cancer drugs that have recently been approved for general clinical use. These compounds bind to the covalent protein-DNA complex and effectively halt the religation of the nicked strand and release of the enzyme from the DNA. We recently determined the structures of human topo I in both covalent and non-covalent complex with double-stranded DNA to 2.1 and 2.5 E resolution.